Bulk RNA sequencing for gene expression profiling of iPSC-derived liver sinusoidal endothelial cells and arterial endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE307468 | GEO | 2025/10/31
REPOSITORIES: GEO
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Project description:The liver is enriched in innate lymphocytes, including Natural Killer (NK) cells, that can continuously interact with Liver Sinusoidal Endothelial Cells (LSECs) within liver sinusoids. NK cells provide the early defence against infections and malignancies by exerting cytotoxicity and by secreting pro-inflammatory cytokines. To decipher how LSECs affect NK cell phenotype and function, we co-cultured NK cells with LSECs and used microarray technology to identify transcriptomic changes.
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Project description:Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue turnover waste macromolecules from blood. LSECs also participate in liver immune responses. A challenge when studying LSEC biology is the rapid loss of the in vivo cell phenotype in culture. In this study, we have examined biological processes and pathways affected during early-stage primary culture of rat LSECs and checked for cell responses to the pro-inflammatory cytokine interleukin (IL)-1 and the anti-inflammatory drug dexamethasone. Methods: LSECs from male Sprague Dawley rats were cultured on type I collagen in a 5% oxygen atmosphere in DMEM with serum-free supplements for 2 and 24 h. Quantitative proteomics using tandem mass tag technology were used to examine proteins in cells and supernatants. Validation was done with ELISA and multiplex immunobead assays, cell ultrastructure was examined by scanning electron microscopy, and scavenger function by quantitative endocytosis assays. Results: LSECs cultured for 24 h showed a characteristic pro-inflammatory phenotype both in the presence and absence of IL-1, displaying upregulation of cellular responses to cytokines and interferon-, cell-cell adhesion, and glycolysis, and downregulation of membrane/endocytosis receptors (MCAM, STAB1, STAB2, LYVE1, CLEC4G) and proteins involved in pyruvate metabolism, citric acid cycle, fatty acid elongation, amino acid metabolism, and oxidation-reduction processes. Dexamethasone improved LSEC viability in culture and repressed the culture-induced stimulation of glycolysis, inflammatory and immune regulatory pathways, and secretion of pro-inflammatory cytokines while increasing IL-10 secretion compared to time-matched control. The number of sieve plates in LSECs was reduced at 24 h both in the presence and absence of dexamethasone but the dexamethasone-treated cells showed a more quiescent phenotype. Conclusion: Rat LSECs become activated towards a pro-inflammatory phenotype during early culture. Dexamethasone represses LSEC activation and improves cell viability.
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Project description:Dysfunction of liver endothelial cells (ECs), especially sinusoid endothelial cells (LSECs), play a key role in progression of liver fibrosis/cirrhosis. Here, we reported a map which reveals heterogeneity and spatial distribution of liver ECs in normal versus cirrhotic mouse liver and determined liver zonal specific transcriptomic changes of LSECs associated with liver cirrhosis using single-cell RNA sequencing technology. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs (arterial and central venous ECs) and 1 cluster of lymphatic ECs. Particularly, we mapped the 3 clusters of LSECs in Zone1-3. We found that liver EC identities are conserved even in liver cirrhosis and that Zone3 LSECs are most susceptible to damages associated with liver cirrhosis with increased capillarization and decreased abilities to regulate endocytosis and vascular tone. Altogether, this study deepens our knowledge for the pathophysiology of cirrhosis at a spatial and cell-specific level, which are indispensable for the development of novel therapeutic strategies to target liver ECs.
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Project description:In human F8 deficiency leads to hemophilia A and is largely synthesized and secreted by the sinusoidal endothelial cells of the liver (LSECs). However, the specificity and characteristics of these cells is not well known. In this study, we performed genome wide expression and CpG methylation profiling of fetal and adult human LSECs together with other fetal endothelial cells, from lung (micro-vascular and arterial), and heart (micro-vascular). Our results reveal plenty of expression and methylation markers distinguishing LSECs at both fetal and adult stages. Differential gene expression of fetal LSECs in comparison to other fetal endothelial cells pointed to several differential regulated pathways and functions in fetal LSECs. We used targeted bisulfite re-sequencing to confirm selected top differentially methylated regions. We further designed an assay where we used the selected methylation markers to test the degree of similarity of in house iPSs generated vascular endothelial cells to fetal and adult LSECs; a higher similarity was found to the fetal than to adult LSECs. Our molecular profiling study provides a guide to test the effectiveness of production of in vitro differentiated LSECs that could be used in cellular therapies. In-silico analysis to identify molecular signature of liver sinusoidal endothelial cells in comparison to other endohtelial cells
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Project description:In human F8 deficiency leads to hemophilia A and is largely synthesized and secreted by the sinusoidal endothelial cells of the liver (LSECs). However, the specificity and characteristics of these cells is not well known. In this study, we performed genome wide expression and CpG methylation profiling of fetal and adult human LSECs together with other fetal endothelial cells, from lung (micro-vascular and arterial), and heart (micro-vascular). Our results reveal plenty of expression and methylation markers distinguishing LSECs at both fetal and adult stages. Differential gene expression of fetal LSECs in comparison to other fetal endothelial cells pointed to several differential regulated pathways and functions in fetal LSECs. We used targeted bisulfite re-sequencing to confirm selected top differentially methylated regions. We further designed an assay where we used the selected methylation markers to test the degree of similarity of in house iPSs generated vascular endothelial cells to fetal and adult LSECs; a higher similarity was found to the fetal than to adult LSECs. Our molecular profiling study provides a guide to test the effectiveness of production of in vitro differentiated LSECs that could be used in cellular therapies. In-silico analysis to identify molecular signature of liver sinusoidal endothelial cells in comparison to other endohtelial cells
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Project description:In human F8 deficiency leads to hemophilia A and is largely synthesized and secreted by the sinusoidal endothelial cells of the liver (LSECs). However, the specificity and characteristics of these cells is not well known. In this study, we performed genome wide expression and CpG methylation profiling of fetal and adult human LSECs together with other fetal endothelial cells, from lung (micro-vascular and arterial), and heart (micro-vascular). Our results reveal plenty of expression and methylation markers distinguishing LSECs at both fetal and adult stages. Differential gene expression of fetal LSECs in comparison to other fetal endothelial cells pointed to several differential regulated pathways and functions in fetal LSECs. We used targeted bisulfite re-sequencing to confirm selected top differentially methylated regions. We further designed an assay where we used the selected methylation markers to test the degree of similarity of in house iPSs generated vascular endothelial cells to fetal and adult LSECs; a higher similarity was found to the fetal than to adult LSECs. Our molecular profiling study provides a guide to test the effectiveness of production of in vitro differentiated LSECs that could be used in cellular therapies. In-silico analysis to identify molecular signature of liver sinusoidal endothelial cells in comparison to other endohtelial cells
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Project description:Endothelial cells (EC) lining arteries and veins have distinct molecular and functional signatures. The (epi)genetic regulatory mechanisms underlying this heterogeneity in human EC are incompletely understood. Using genome-wide microarray screening we established a specific fingerprint of freshly isolated arterial (HUAEC) and venous EC (HUVEC) from human umbilical cord comprising 64 arterial and 12 venous genes, representing distinct functions and pathways. Among the arterial genes were 8 transcription factors, including HEY2, a downstream target of Notch signaling and the current ‘golden standard’ pathway for arterial EC specification. Short-term culture of HUAEC or HUVEC abrogated differential gene expression resulting in a default state. Erasure of arterial gene expression was at least in part due to loss of canonical Notch activity and HEY2 expression. Notably, nCounter analysis revealed that restoring HEY2 expression or Delta-like 4 (Dll4)-induced Notch signaling in cultured HUVEC or HUAEC only partially reinstated the arterial EC gene signature while combined overexpression of the 8 transcription factors restored this fingerprint much more robustly. Each transcription factor had a different impact on gene regulation, with some stimulating only few and others boosting a large proportion of arterial genes. Interestingly, although there was some overlap and cross-regulation, the transcription factors largely complemented each other in regulating the arterial EC gene profile. Thus, our study showed that Notch signaling determines only part of the arterial EC signature and identified additional novel and complementary transcriptional players in the complex regulation of human arteriovenous EC identity To identify an arteriovenous (AV) fingerprint in human endothelial cells (EC) across different vascular beds, we used microarrays on RNA from 38 EC samples corresponding to 6 cultured human arterial-EC types (hepatic artery EC or HHAEC, N=3; aorta EC or HAEC, N=2; coronary artery EC or HCAEC, N=2; iliac artery EC or HIAEC, N=2; pulmonary artery EC or HPAEC, N=3; and umbilical artery EC or HUAEC-C, N=5), 4 cultured human venous-EC types (hepatic vein EC or HHVEC, N=3; iliac vein EC or HIVEC, N=3; pulmonary vein EC or HPVEC, N=2; and umbilical vein EC or HUVEC-C, N=5), freshly isolated HUAEC (HUAEC-F, N=4) and freshly isolated HUVEC (HUVEC-F, N=4). Due to the difficulty to obtain biopsies from healthy donors, we did not have access to freshly isolated aEC or vEC matched for all cultured EC types.
2014-01-07 | E-GEOD-43475 | biostudies-arrayexpress